It has been known that, in organisms such as typically mammals, histamine that is a physiologically-active endogenous factor functions as a neurotransmitter and has extensive pharmacological activities (for example, see Life Science, Vol. 17, p. 503 (1975)).
Immunohistochemical studies have made it clear that a histamine-agonistic (producing) cell body exists in the nodal papillary nucleus in a posterior hypothalamic region and that histamine-agonistic nerve fibers project histamine in an extremely broad range in the brain, which supports various pharmacological effects of histamine (for example, see Journal of Comprehensive Neurology, Vol. 273, p. 283).
The existence of histamine-agonistic nerves in the nodal papillary nucleus in a posterior hypothalamic region suggests that histamine may have an important role in control of physiological functions relating to brain functions, especially to hypothalamic functions (sleep, vigilance rhythm, incretion, eating and drinking action, sexual action, etc.) (for example, see Progress in Neurobiology, Vol. 63, p. 637 (2001)).
The projection of histamine-agonistic nerve fibers to the brain region that relates to vigilance sustenance (e.g., cerebral cortex) suggests the role of histamine in control of vigilance or vigilance-sleep cycle. The projection of histamine-agonistic nerve fibers to many peripheral structures such as hippocampus and amygdaloid complex suggests the role of histamine in control of autonomic nerves, emotion, control of motivated action and learning/memory process.
When released from producing cells, histamine acts with a specific polymer that is referred to as a receptor on the surface of a cell membrane or inside a target cell, therefore exhibiting its pharmacological effects for control of various body functions. Heretofore, four types of histamine receptors have been found. In particular, the presence of a histamine receptor that participates in the central and peripheral nervous functions, a histamine-H3 receptor, has been shown by various pharmacological and physiological studies (for example, see Trends in Pharmacological Science, Vol. 8, p. 24 (1986)). Recently, human and rodent histamine-H3 receptor genes have been identified and their existence has been revealed (for example, see Molecular Pharmacology, Vol. 55, p. 1101 (1999)).
The histamine-H3 receptor exists in the presynaptic membrane of central or peripheral neurocytes and functions as a self-receptor, therefore controlling the release of histamine and controlling the release of other neurotransmitters. Specifically, a histamine-H3 receptor agonist, or its antagonist or inverse-agonist controls the release of histamine, noradrenaline, serotonin, acetylcholine or dopamine from nerve ending. The release of these neurotransmitters is inhibited by a histamine-H3 receptor agonist such as (R)-(α)-methylhistamine, and is promoted by a histamine-H3 receptor antagonist or inverse-agonist such as thioperamide (for example, see Trends in Pharmacological Science, Vol. 19, p. 177 (1998)).